With an estimated 170 million people worldwide infected with the hepatitis C virus (HCV), chronic hepatitis C infection is an important global health problem. HCV infection is the principal cause of chronic liver disease and hepatocellular carcinoma and the leading indication for liver transplantation in the United States and Western Europe. The only marketed products that have shown to eradicate HCV are interferons, either in mono- or in combination therapy.
The hepatitis C virus is unique in that it is a single-stranded, RNA-based virus that targets hepatocytes for infection and replication of new virions. About 4-8 weeks after the initial HCV infection, acute elevations of hepatic transaminase levels in serum are often noted, signalling that inflammation in the liver is occurring. Approximately 80% of patients with HCV infection progress to more chronic liver disease. Further progression of the disease leads to scarring or fibrosis, and cirrhosis in the affected regions of the liver in approximately 20 to 50% of infected patients between 10 to 20 years after the initial infection. A number of patients with chronic HCV infection may also progress to primary hepatocellular carcinoma.
Human recombinant IFNα2b is approved in many countries for the treatment of hepatitis B and C infection, either as a monotherapy or in combination with ribavirin. In addition, it is also approved in many countries for treating patients with cancer. IFNα2b is available as Intron® A (Schering), which needs to be administered three times a week due to the relatively short half life of 2-3 h after subcutaneous (SC) injection. A longer-acting version of IFNα2b has been developed, by polyethylene glycol modification of the molecule. Pegylated IFNα2b (PEGIntron®) is only approved for the treatment of hepatitis C. Its half-life is about 40 h and it is administered once weekly by SC injection. However, PEGIntron®, being a modified IFNα2b molecule, compared to unpegylated INFα2b, it has reduced affinity for the IFNα2b receptor, distributes differently in the body and hence its safety and efficacy are not necessarily comparable to IFNα2b.
Other long-acting INF therapies are under development. Like PEG-Intron these are not based on controlled release of INF, but on a prolonged half-life owing to delayed clearance.
In current methods of treating HCV infection, the goal is SVR (sustained viral response), which is defined as finding no detectable HCV 24 weeks after completion of therapy. It is recognized that predictive factors for SVR are EVR (early viral response), which may be described as at least a 2 log drop in serum HCV RNA level compared to baseline (pretreatment level) after 12 weeks of treatment, and, increasingly, RVR (rapid viral response), which is defined as no detectable HCV after 4 weeks of treatment. Additionally, these predictive factors are important per se, as not all patients respond to INF (combined) therapy, and it is therefore preferred to have an indication of response at an early point in time during therapy, e.g. to avoid the adverse events and expense of futile therapy.
INF therapy, particularly at higher doses as is known from cancer treatment, is frequently accompanied by uncomfortable or even inhibitory side effects.
Desires in HCV infection therapy are, inter alia, obtaining an improved RVR and/or EVR, a better side effect profile, and/or a better ratio between therapeutic effect and side effects.